Adiponectin receptor-1 expression is associated with good prognosis in gastric cancer

<p>Abstract</p> <p>Background</p> <p>Adiponectin is inversely related to BMI, positively correlates with insulin sensitivity, and has anti-atherogenic effects. In recent years, adiponectin has been well studied in the field of oncology. Adiponectin has been shown to have antiproliferative effects on gastric cancer, and adiponectin expression is inversely correlated with clinical staging of the disease. However, no studies have reported the correlation between serum adiponectin and receptor expression with disease progression.</p> <p>Methods</p> <p>In this study, we evaluated expression levels of 2 adiponectin receptors--AdipoR1 and AdipoR2--and attempted to correlate their expression with prognosis in gastric cancer patients. AdipoR1 and AdipoR2 expression in gastric cancer cell lines (MKN45, TMK-1, NUGC3, and NUGC4) was evaluated by western blotting analysis, and the antiproliferative potential of adiponectin was examined in vitro. Serum adiponectin levels were evaluated in 100 gastric cancer patients, and the expression of AdipoR1 and AdipoR2 was assessed by immunohistochemical staining.</p> <p>Results</p> <p>MKN45 and NUGC3 expressed higher levels of AdipoR1 compared to NUGC4, even though there was no significance in AdipoR2 expression. The antiproliferative effect of adiponectin was confirmed in MKN45 and NUGC3 at 10 μg/ml. No significant associations were observed between serum adiponectin levels and clinicopathological characteristics, but lymphatic metastasis and peritoneal dissemination were significantly higher in the negative AdipoR1 immunostaining group (24/32, <it>p </it>= 0.013 and 9/32, <it>p </it>= 0.042, respectively) compared to the positive AdipoR1 group (lymphatic metastasis, 33/68; peritoneal dissemination, 8/68). On the other hand, AdipoR2 expression was only associated with histopathological type (<it>p </it>= 0.001). In survival analysis, the AdipoR1 positive staining group had significantly longer survival rates than the negative staining group (<it>p </it>= 0.01). However, multivariate analysis indicated that AdipoR1 was not an independent prognostic factor on patient's survival on gastric cancer.</p> <p>Conclusions</p> <p>In gastric cancer, adiponectin has the possibility to be involved in cell growth suppression via AdipoR1. The presence of AdipoR1 could be a novel anticancer therapeutic target in gastric cancer.</p

Design and development of a peptide-based adiponectin receptor agonist for cancer treatment

<p>Abstract</p> <p>Background</p> <p>Adiponectin, a fat tissue-derived adipokine, exhibits beneficial effects against insulin resistance, cardiovascular disease, inflammatory conditions, and cancer. Circulating adiponectin levels are decreased in obese individuals, and this feature correlates with increased risk of developing several metabolic, immunological and neoplastic diseases. Thus, pharmacological replacement of adiponectin might prove clinically beneficial, especially for the obese patient population. At present, adiponectin-based therapeutics are not available, partly due to yet unclear structure/function relationships of the cytokine and difficulties in converting the full size adiponectin protein into a viable drug.</p> <p>Results</p> <p>We aimed to generate adiponectin-based short peptide that can mimic adiponectin action and be suitable for preclinical and clinical development as a cancer therapeutic. Using a panel of 66 overlapping 10 amino acid-long peptides covering the entire adiponectin globular domain (residues 105-254), we identified the 149-166 region as the adiponectin active site. Three-dimensional modeling of the active site and functional screening of additional 330 peptide analogs covering this region resulted in the development of a lead peptidomimetic, ADP 355 (H-DAsn-Ile-Pro-Nva-Leu-Tyr-DSer-Phe-Ala-DSer-NH₂). In several adiponectin receptor-positive cancer cell lines, ADP 355 restricted proliferation in a dose-dependent manner at 100 nM-10 μM concentrations (exceeding the effects of 50 ng/mL globular adiponectin). Furthermore, ADP 355 modulated several key signaling pathways (AMPK, Akt, STAT3, ERK1/2) in an adiponectin-like manner. siRNA knockdown experiments suggested that ADP 355 effects can be transmitted through both adiponectin receptors, with a greater contribution of AdipoR1. <it>In vivo</it>, intraperitoneal administration of 1 mg/kg/day ADP 355 for 28 days suppressed the growth of orthotopic human breast cancer xenografts by ~31%. The peptide displayed excellent stability (at least 30 min) in mouse blood or serum and did not induce gross toxic effects at 5-50 mg/kg bolus doses in normal CBA/J mice.</p> <p>Conclusions</p> <p>ADP 355 is a first-in-class adiponectin receptor agonist. Its biological activity, superior stability in biological fluids as well as acceptable toxicity profile indicate that the peptidomimetic represents a true lead compound for pharmaceutical development to replace low adiponectin levels in cancer and other malignancies.</p

Whole genome analysis of a schistosomiasis-transmitting freshwater snail

Biomphalaria snails are instrumental in transmission of the human blood fluke Schistosoma mansoni. With the World Health Organization's goal to eliminate schistosomiasis as a global health problem by 2025, there is now renewed emphasis on snail control. Here, we characterize the genome of Biomphalaria glabrata, a lophotrochozoan protostome, and provide timely and important information on snail biology. We describe aspects of phero-perception, stress responses, immune function and regulation of gene expression that support the persistence of B. glabrata in the field and may define this species as a suitable snail host for S. mansoni. We identify several potential targets for developing novel control measures aimed at reducing snail-mediated transmission of schistosomiasis

DNA damage in obesity: Initiator, promoter and predictor of cancer

Epidemiological evidence linking obesity with increased risk of cancer is steadily growing, although the causative aspects underpinning this association are only partially understood. Obesity leads to a physiological imbalance in the regulation of adipose tissue and its normal functioning, resulting in hyperglycaemia, dyslipidaemia and inflammation. These states promote the generation of oxidative stress, which is exacerbated in obesity by a decline in anti-oxidant defence systems. Oxidative stress can have a marked impact on DNA, producing mutagenic lesions that could prove carcinogenic. Here we review the current evidence for genomic instability, sustained DNA damage and accelerated genome ageing in obesity. We explore the notion of genotoxicity, ensuing from systemic oxidative stress, as a key oncogenic factor in obesity. Finally, we advocate for early, pre-malignant assessment of genome integrity and stability to inform surveillance strategies and interventions

Geoeconomic variations in epidemiology, ventilation management, and outcomes in invasively ventilated intensive care unit patients without acute respiratory distress syndrome: a pooled analysis of four observational studies

Background: Geoeconomic variations in epidemiology, the practice of ventilation, and outcome in invasively ventilated intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) remain unexplored. In this analysis we aim to address these gaps using individual patient data of four large observational studies. Methods: In this pooled analysis we harmonised individual patient data from the ERICC, LUNG SAFE, PRoVENT, and PRoVENT-iMiC prospective observational studies, which were conducted from June, 2011, to December, 2018, in 534 ICUs in 54 countries. We used the 2016 World Bank classification to define two geoeconomic regions: middle-income countries (MICs) and high-income countries (HICs). ARDS was defined according to the Berlin criteria. Descriptive statistics were used to compare patients in MICs versus HICs. The primary outcome was the use of low tidal volume ventilation (LTVV) for the first 3 days of mechanical ventilation. Secondary outcomes were key ventilation parameters (tidal volume size, positive end-expiratory pressure, fraction of inspired oxygen, peak pressure, plateau pressure, driving pressure, and respiratory rate), patient characteristics, the risk for and actual development of acute respiratory distress syndrome after the first day of ventilation, duration of ventilation, ICU length of stay, and ICU mortality. Findings: Of the 7608 patients included in the original studies, this analysis included 3852 patients without ARDS, of whom 2345 were from MICs and 1507 were from HICs. Patients in MICs were younger, shorter and with a slightly lower body-mass index, more often had diabetes and active cancer, but less often chronic obstructive pulmonary disease and heart failure than patients from HICs. Sequential organ failure assessment scores were similar in MICs and HICs. Use of LTVV in MICs and HICs was comparable (42\ub74% vs 44\ub72%; absolute difference \u20131\ub769 [\u20139\ub758 to 6\ub711] p=0\ub767; data available in 3174 [82%] of 3852 patients). The median applied positive end expiratory pressure was lower in MICs than in HICs (5 [IQR 5\u20138] vs 6 [5\u20138] cm H2O; p=0\ub70011). ICU mortality was higher in MICs than in HICs (30\ub75% vs 19\ub79%; p=0\ub70004; adjusted effect 16\ub741% [95% CI 9\ub752\u201323\ub752]; p&lt;0\ub70001) and was inversely associated with gross domestic product (adjusted odds ratio for a US$10 000 increase per capita 0\ub780 [95% CI 0\ub775\u20130\ub786]; p&lt;0\ub70001). Interpretation: Despite similar disease severity and ventilation management, ICU mortality in patients without ARDS is higher in MICs than in HICs, with a strong association with country-level economic status. Funding: No funding

Corrigendum: Whole genome analysis of a schistosomiasis-transmitting freshwater snail

This corrects the article DOI: 10.1038/ncomms15451

Соціальний маркетинг у благодійних організаціях: модель послідовного посередництва

Благодійні організації відграють значну роль у сучасному суспільстві на противагу органам державного управління чи суб’єктам підприємницької діяльності. Місія благодійних організацій є широкомасштабною та починається від забезпечення продуктами харчування жертв стихійних лих до надання притулку біженцям, які рятуються від воєнних конфліктів та політичних переслідувань. Однак, для досягнення вищезазначених цілей благодійні організації потребують підтримки фізичних осіб у вигляді фінансових та часових ресурсів (волонтерська робота). Автори зазначають, що благодійні організації виступають у ролі посередницького апарату та передають ресурси від вищого (які прагнуть допомогти) до малозабезпеченого класу суспільства. Таким чином, визначення ролі пожертв фізичних осіб для благодійних організацій з маркетингової точки зору є актуальним. У статті проаналізовано сприйняття ролі та ставлення до благодійних організацій з боку суспільства. Авторами зазначено, що низка факторів поведінки та сприйняття впливають на: благодійні наміри фізичних осіб (включаючи їх ставлення до таких організацій); готовність допомагати іншим та довіру до неурядових організацій. При цьому авторами визначено, що у раніше проведених дослідженнях науковців встановлено взаємозв’язок між вищезазначеними змінними. Однак, у даних роботах взаємозв’язок між визначеними змінними та благодійними намірами досліджено окремо. Таким чином, автори приходять до висновку, що наразі незрозуміло, яким чином фактори поведінки та сприйняття пов’язані між собою і як вони впливають на благодійні наміри. Головною метою статті є перевірка послідовної посередницької моделі при оцінці ставлення до благодійних організацій та довіри до неурядових організацій у взаємозв’язку між ставленням до допомоги іншим та благодійними намірами. У зв’язку з цим, авторами представлено послідовну посередницьку модель, яка демонструє взаємозв’язок між змінними, вихідні данні для якої були сформовані на основі аналізу даних репрезентативної вибірки 147 респондентів, які проживають у регіоні Мармара, Туреччина. Результати проведеного дослідження свідчать про те, що ставлення до допомоги іншим має позитивний непрямий ефект як на наміри витрачати власний час (волонтерство), так і на наміри фінансувати діяльність благодійних та неурядових організацій. Також авторами відмічено, що довіра до неурядових організацій має позитивний прямий ефект на наміри присвятити час та наміри фінансувати їх функціонування.Charitable organizations play a significant role in today's society that cannot be achieved by governments or businesses. They have missions ranging from providing hot soup to victims after an earthquake to providing shelters to refugees running away from the war. However, in order to achieve these missions, they need the support of individuals in terms of monetary and time donations (voluntary work). Charitable organizations act as intermediaries and they transmit the sources from the wealthy people who want to help the needy. The importance of individual giving for charitable organizations attracted the research in the marketing field and authors examined the role of attitudes and perceptions. A range of attitudinal and perceptual factors can influence individuals' charitable giving intention including attitudes toward charitable organizations, attitudes toward helping others, and trust in the third sector. The prior studies have demonstrated that these variables were interrelated. However, they examined the relationship between these variables and charitable giving intention independently and it is still unclear how these perceptual and attitudinal variables are associated with each other and charitable giving intention. To fill this research gap, the purpose of this study is to test the serial mediating role of attitudes toward charitable organizations and trust in the third sector in the relationship between attitudes toward helping others and charitable giving intention. We, therefore, built a serial mediation model showing the relationship between the variables and tested it with the data obtained from a convenience sample of 417 respondents who live in the Eastern Marmara Region, Turkey. Our findings show that attitudes toward helping others have a positive indirect effect on both intended to give time and intention to give money through attitudes toward charitable organizations and trust in the third sector in sequence. Additionally, attitudes toward charitable organizations have a positive specific indirect effect on the intention to give time and intention to give money in sequence through trust in the third sector. Also, trust in the third sector has a positive direct effect on the intention to give time and intention to give money. These findings indicate that attitudes toward charitable organizations and trust in the third sector sequentially mediate the relationship between intention to give time and intention to give money. The results also suggest that the proposed model explains almost 35% of the variance in intention to give money and 11% of the variance in intention to time

Intelligent modelling of alpha (alpha) parameter; comparison of ANN and ANFIS cases

In this study, intelligent models are proposed for the Alpha (alpha) parameter or so called linewidth enhancement factor (LEF) which is an important parameter influencing many static, dynamic and noise characteristics of semiconductor lasers. The models are obtained with the use of artificial neural network (ANN) and adaptive neuro-fuzzy inference system (ANFIS) approaches. The proposed approaches are in very good agreement with the previously published experimental values